Involvement of novel ubiquitin ligases in the pathogenic mechanism of Alzheimer's disease and drug discovery for fundamental therapeutic agent

2015 Fiscal Year Final Research Report

• Project/Area Number: 24300135
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Kurume University (2013-2015); Yokohama College of Pharmacy (2012)
• Principal Investigator: Nomura Yasuyuki 久留米大学, 医学部, 教授 (00034041)
• Co-Investigator(Kenkyū-buntansha): Sobue Gen 名古屋大学, 医学系研究科, 特任教授 (20148315) ; Okuma Yasunobu 千葉科学大学, 薬学部, 教授 (20127939) ; Kitamura Yoshihisa 立命館大学, 薬学部, 教授 (60195295) ; Tomobe Koji 横浜薬科大学, 薬学部, 准教授 (80460286) ; Kaneko Masayuki 広島大学, 医歯薬保健学研究院(医), 准教授 (10322827)
• Co-Investigator(Renkei-kenkyūsha): Ishigaki Shinsuke 名古屋大学, 医学系研究科, 特任助教 (40378170) ; Takata Kazuyuki 京都薬科大学, 薬学部, 准教授 (10434664) ; Kawada Koichi 千葉科学大学, 薬学部, 講師 (30581631)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Keywords: アルツハイマー病 / ユビキチンリガーゼ / APP / アミロイドβ / ERAD / 酸化ストレス / γ-セクレターゼ / 膜輸送

Outline of Final Research Achievements

We found that the ubiquitin ligase HRD1 is involved in degradation of amyloid precursor protein (APP), which is processed into β-amyloid, the responsible protein for Alzheimer’s disease (AD). Interestingly, HRD1 protein is reduced in the postmortem cerebral cortex of AD patients, possibly because of its protein insolubilization. In this study, we demonstrated the involvement of oxidative stress in HRD1 insolubilization. We also found that ubiquitin ligases, Dorfin (RNF19A) and RNF19B, are involved in Aβ generation through a different mechanism from that of HRD1. In this study, we demonstrated that Dorfin and RNF19B regulate APP processing by γ-secretase through APP trafficking to the lysosome.

Free Research Field

神経化学・神経薬理学